ES2361338T3 - PIRID-2-ONAS 3,5-USEFUL DISPOSED AS INHIBITORS OF THE TEC FAMILY OF TIROSINA KINASES NOT LINKED TO RECEIVER. - Google Patents

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

Technical Field of the Invention

The present invention relates to compounds useful as protein kinase inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases. The invention also provides methods for preparing the compounds of the invention.

Background of the invention

The Tec family of non-receptor-linked tyrosine kinases plays an essential role in signal transmission through antigen receptors such as TCR, BCR and Fcε receptors (reviewed in Miller, et al., Current Opinion in Immunology 14: 331 -340 (2002) The Tec family kinases are essential in the activation of T lymphocytes. Three members of the Tec family, Itk, Rlk and Tec, are activated downstream of the coupling with the antigen receptor in the T lymphocytes and transmit signals to the downstream effectors, including PLC-γ The elimination of Itk in mice results in less proliferation induced by T-lymphocyte receptor (TCR) and secretion of cytokines IL-2, IL-4, IL-5, IL-10 and IFN-γ. (Shaaeffer et al., Science 284; 638-641 (1999)), Fowell et al., Immunity 1; 399-409 (1999), Schaeffer et al. Nature Immunology 2, 12; 1183-1188 (2001))). The immunological symptoms of allergic asthma are attenuated in Itk - / - mice. Pulmonary inflammation, eosinophilic infiltration and mucosal production are drastically reduced in Itk - / - mice in response to the challenge test with the OVA allergen (Mueller et al., Journal of Immunology 170: 5056-5063 (2003)). Itk has also been associated with atopic dermatitis. It has been shown that this gene is expressed more intensely in peripheral blood T lymphocytes of patients with severe and / or moderate atopic dermatitis than in controls or in patients with mild atopic dermatitis (Matsumoto et al., Internation archives of Allergy and Immunology 129: 327-340 (2002)).

The kinases of the Tec family are also essential for the development and activation of B lymphocytes. Patients with Btk mutations have a strong blockage in the development of B lymphocytes, which results in the practical absence of B lymphocytes and plasmocytes, at very low levels of Ig and a strong inhibition of the humoral response for antigen recruitment (reviewed in Vihinen et al., Frontiers in Bioscience 5: d917-928).

Tec kinases also play a role in mast cell activation through the high affinity IgE receptor (FcERI). Itk and Btk are expressed in mast cells and activated by crosslinking of FcεRI (Kawakami et al., Journal of Immunology; 3556-3562 (1995)). Btk-deficient murine mast cells show reduced degranulation and reduced production of pro-inflammatory cytokines after cross-linking of FcεRI (Kawakami et al., Journal of leukocyte biology 65: 286-290). Btk deficiency also results in a decrease in the functions of the macrophage effector (Mukhopadhyay et al., Journal of Immunology; 168, 2914-2921 (2002)).

Therefore, there is a great need to develop compounds useful as protein kinase inhibitors. In particular, it would be desirable to develop compounds that are useful as protein kinase inhibitors of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx / Txk / Rlk).

WO 02/079192 A1 describes compounds that inhibit the tyrosine kinase enzymes thereby making them useful as anti-cancer agents. These compounds include a benzimidazol-1H-pyridin-2-one structure.

Summary of the invention

The present invention relates to compounds and compositions useful as protein kinase inhibitors. The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as protein kinase inhibitors. In certain embodiments, these compounds are effective as protein kinase inhibitors of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk). These compounds have formula I, as defined above, or a pharmaceutically acceptable salt thereof.

These pharmaceutically acceptable compounds and compositions thereof are useful for treatment.

or the prevention of a variety of diseases, disorders or conditions, including but not limited to, autoimmune, inflammatory, proliferative or hyperproliferative disease or a disease with immunological intervention. These compounds and compositions are also useful in methods to prevent platelet aggregation induced by thrombin. The compounds provided by means of the present invention are also useful for the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction mechanisms with the intervention of said kinases; and the comparative evaluation of new kinase inhibitors.

Detailed description of the invention

The present invention provides compounds of Formula I:

image 1

Formula I

5 or pharmaceutically acceptable salts thereof, wherein R2 is a 6-membered aryl ring or a 6-membered heteroaryl ring having 0-2 nitrogen atoms, said ring being optionally substituted with up to five JR2; each R3 and R4 is independently H, halogen or C1-4 aliphatic optionally substituted with 0-5 presence of halogen, OH, OCH3, OCF3, NO2, NH2, CN, NHCH3, SCH3, N (CH3) 2 or C1-2 aliphatic optionally substituted 0-5

10 times with F;

You see

image 1

wherein V is optionally and independently substituted with 0-2 presence of halogen, C1-2 aliphatic, C1-2 haloaliphatic, OH, OCH3, OCF3 or CN; R is H or unsubstituted C1-6 aliphatic; R1

is independently H, halogen, CN, NO2 or C1-4 aliphatic optionally substituted with 0-4 presence of halogen, C1-2 aliphatic, CF3, OH, OCH3, OCF3, NO2, NH2, CN, NHCH3, SCH3 or N (CH3 )2;

Z is (T) n-Q;

20 T is a C1-6 aliphatic chain, in which up to three methylene units of the chain are optionally and independently replaced by -NR5-, -O-, -S-, -SO-, -SO2-, -CS- or -CO-; T is optionally substituted with 0-3 JT;

Q is a 3-8 membered, saturated, partially unsaturated or completely unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; or is a bicyclic ring system, 8-12 members, saturated, partially unsaturated or completely unsaturated having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; Q is optionally substituted with 0-5

JQ

;

n is0ó1;

R5

30 is H, C1-6 aliphatic, C3-6 cycloaliphatic, phenyl, benzyl, CO (C1-4 aliphatic) or -SO2 (C1-6 aliphatic), each R5 being optionally substituted with 0-5 JR5 groups; each of JT and JR5 is independently H, C3-6 cycloaliphatic, C1-6 aliphatic, halogen, NO2, CN, -NH2, NH (C1-4 aliphatic), -N (C1-4 aliphatic) 2, -OH, -O (C1-4 aliphatic), -CO2H, -CO2 (C1-4 aliphatic), O (C1-4 haloaliphatic) or halo (C1-4 aliphatic);

Each of JR2, JQ, Jx and JY is independently halogen, -NO2, -CN, U, - (U) m- (C6-10 aryl), - (U) m- (5-12 membered heteroaryl) , - (U) m- (3-12 membered heterocyclyl), - (U) m- (C3-10 cycloaliphatic), -OR0, -SR0, N (R0) 2, - (C1-6 alkyl) -OR0 , - (C1-6 alkyl) -N (R0) 2, - (C1-6 alkyl) -SR0, -NR0C (O) R0, NR0C (S) R0, NR0C (O) N (R0) 2, -NR0C (S) N (R0) 2, NR0CO2R0, -NR0NR0C (O) R0, -NR0NR0C (O) N (R0) 2, NR0NR0CO2R0, -C (O) C (O) R0, -C (O) CH2C (O ) R0, -CO2R0, -C (O) R0, -C (S) R0, -C (O) N (R0) 2,

40 C (S) N (R0) 2, -OC (O), N (R0) 2, -OC (O) R0, -C (O) N (OR0) R0, -C (NOR0) R0, -S (O) 2R0, -S (O) 3R0, SO2N (R0) 2, -S (O) R0, -NR0SO2N (R0) 2, -NR0SO2R0, -N (OR0) R0, -C (= NH) -N (R0) 2, -P (O) 2R0, -PO (R0) 2, -OPO (R0) 2, = O, = S, = NHHR0, = NN (R0) 2, = NNHC (O) R0, = NNHCO2 (C1-6 alkyl), = NNHSO2 (C1-6 alkyl), = NOH or = NR0; each JR2, JQ, JX and JY being optional and independently substituted with 05 RX;

45 U is a C1-10 alkylidene chain, in which up to three methylene units of the chain are independently replaced by -NR0, -O-, -S-, -SO-, SO2-or -CO-; m es0ó1 each Rx is independently halogen, NO2, CN, NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, OH,

O (C1-4 aliphatic), O (C1-4 haloaliphatic), CO (C1-4 aliphatic), CO2H, CO2 (C1-4 aliphatic), C1-6 aliphatic,

C1-4 haloaliphatic, phenyl, -O (Ph), 5-6 membered heteroaryl, C3-8 cycloaliphatic, 5-8 heterocyclyl

members, -C 1-6 aliphatic- (Ph), -C 1-6 alkyl- (5-6 membered heteroaryl), -C 1-6 alkyl- (cycloaliphatic

C3-8), -C 1-8 alkyl- (5-8 membered heterocyclyl) or a C1-10 alkylidene chain in which up to

2 methylene units of the chain are optionally replaced with O, N or S; being

each Rx optional and independently substituted with 0-5 J0; each R0 is independently H, aliphatic C1-6, haloaliphatic C1-4, CO (aliphatic C1-4), CO2 (aliphatic C1-4),

SO2 (C1-4 aliphatic), -SO2 (phenyl), phenyl, 5-6 membered heteroaryl, 5-8 membered heterocyclyl,

C3-8 cycloaliphatic, -C1-6- (Ph) aliphatic -C 1-6 alkyl- (5-6 membered heteroaryl), -C 1-6 alkyl

(5-8 membered heterocyclyl), -C 1-6 alkyl- (C 3-8 cycloaliphatic); or a C1-10 alkylidene chain

in which up to 2 methylene units of the chain are optionally replaced by O, N

or S; said R0 being optionally substituted with 0-5 J0;

or two R0, on the same substituent or on different substituents, taken together with the atom or atoms to which each R0 is attached, form a 3-8 membered monocyclic or bicyclic ring, saturated, partially unsaturated or completely unsaturated, which it has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally and independently substituted with 0-4 presence of halogen, NO2, CN, C1-4 aliphatic, NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, OH, O (C1- aliphatic 4), CO2H, CO2 (C1-4 aliphatic), O (C1-4 haloaliphatic) or C1-4 haloaliphatic, in which each of the C1-4 aliphatic groups of R0 is unsubstituted; Each J0 is independently halogen, NO2, CN, C1-4 aliphatic, -NH2, -NH (C1-4 aliphatic), -N, -O (C1-4 aliphatic), - CO2H, -CO2 (C1-4 aliphatic), -O (C1-4 haloaliphatic) or halo (C1-4 aliphatic), in which each of the C1-4 aliphatic groups J0 of R0 is unsubstituted.

The compounds of the present invention include those described generally above, and are further illustrated by the classes, subclasses and species disclosed herein. As used herein, the following definitions apply unless otherwise specified. For the purposes of the present invention, chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th ed., Ed .: Smith, M.B. and March, J., John Wiley and Sons, New York: 2001.

As described herein, a specified number of atoms interval includes any integer contained in the range. For example, a group that has 1-4 atoms can have 1, 2, 3 or 4 atoms.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents, as illustrated above in general, or as exemplified by the particular classes, subclasses and species of the invention. It should be appreciated that the expression "optionally substituted" is used interchangeably with the expression "substituted or unsubstituted". In general, the term "substituted", whether or not accompanied by the expression "optionally", refers to the replacement of hydrogen radicals in a structure given by the radical of a specified substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each of the positions that may be substituted for the group, and when more than one position in a given structure may be substituted with more than one substituent selected from a group specified, the substituent may have the same or different position. Preferably, the combinations of substituents included in the present invention are those that result in the formation of stable or chemically viable compounds.

The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions that allow their production, detection and preferably recovery, purification and use for one or more of the disclosed purposes. in the present document. In some embodiments, a stable compound or a chemically viable compound is one that does not undergo significant alteration when subjected to a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least one week.

The term "aliphatic" or "aliphatic group", as used herein, means a hydrocarbon chain, linear (ie, unbranched) or branched, substituted or unsubstituted, that is completely saturated or that contains one or more units of unsaturation and that has a single point of attachment with the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear, branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Specific examples include methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl and tert-butyl.

The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl" or "cycloalkyl") refers to a monocyclic C3-C8 hydrocarbon or a bicyclic C8-C12 hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but which is not aromatic, which has a single point of attachment with the rest of the molecule, in which any single ring of said bicyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include cyclohexyl, cyclopropenyl and cyclobutyl. The term "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic", as used herein, refers to non-aromatic, monocyclic, bicyclic or tricyclic ring systems in which one or more ring members are a heteroatom independently selected. In some embodiments, the "heterocycle", "heterocyclyl", "heterocycloaliphatic" or "heterocyclic" group has 14 ring members, of which one or more ring members is a heteroatom that is independently selected from oxygen, nitrogen or phosphorus, and each ring of the system contains 3 to 7 ring members.

Suitable heterocycles include, but are not limited to, 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2 -morpholino, 3-morpholino, 4morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1tetrahydropyrazinyl, 2-tetrahydropyrazinyl, 3-tetrahydropyrazinyl, 1-piper , 3-piperidinyl, 1pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imzolidinyl, 1-imzolidinyl -imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithian and 1,3-dihydro-imidazol-2-one.

Cyclic groups (for example, cycloaliphatic and heterocycles) can be linearly condensed, bridged or spiro-cyclic.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen or; a nitrogen of a susceptible heterocyclic ring of substitution, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in pyrrolidinyl with N substitution)).

The term "unsaturated," as used herein, means that a remainder has one or more units of unsaturation.

The term "completely unsaturated", when referring to a ring, means an aromatic ring.

The terms "alkoxy" or "thioalkyl," as used herein, refer to an alkyl group, as previously defined, attached to the main carbon chain through an oxygen atom ("alkoxy") or of sulfur ("thioalkyl").

The terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The terms "halogen", "halo" and "hal" mean F, Cl, Br

or I.

The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen members. , in which at least one ring of the system is aromatic and in which each ring of the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the expression "aryl ring". The term "aryl" also refers to heteroaryl ring systems as defined below.

The term "heteroaryl", used alone or as part of a larger residue such as "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic systems having a total of five to fourteen ring members, in the that at least one ring of the system is aromatic, at least one ring of the system contains one or more heteroatoms, and in which each ring of the system contains 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic." Suitable heteroaryl rings include, but are not limited to, 2-furanyl, 3-furanyl, Nimidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2oxazolyl, 4 -oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example, 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (for example, 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (for example, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (for example 1-isoquinolinyl, 3-isoqui nolinyl or 4-isoquinolinyl).

The term "alkylidene chain" refers to a linear or branched hydrocarbon chain that can be completely saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

The term "protecting group", as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multi-functional compound. In certain embodiments, the protecting group has one or more, or preferably all, of the following characteristics: a)

5

10

fifteen

twenty

25

30

reacts selectively with good yield to give a protected substrate that is stable to the reactions that take place at one or more of the other reactive sites; and b) it can be selectively removed with good performance by reagents that do not attack the regenerated functional group. Examples of protective groups are detailed in Greene, T.W., Wuts, P.G. in "Protective Groups in Organic Synthesis", third edition, John Wiley and Sons, New York: 1999.

In some embodiments, an alkyl or aliphatic chain may be optionally interrupted with another atom or group. This means that, optionally, a methylene unit of the alkyl or aliphatic chain can be substituted by said other atom or group. Examples of such atoms or groups include, but are not limited to, -NR-, -O-, -S-, -CO2-, -OC (O) -, -C (O) CO-, -C (O) - , -C (O) NR-, -C (= N-CN), -NRCO-, -NRC (O) O-, -SO2NR-, -NRSO2-, NRC (O) NR-, -OC (O) NR-, -NRSO2NR-, -SO-or -SO2-, in which R is as defined herein. Unless otherwise specified, the optional substitutions form a chemically stable compound. Optional interruptions can take place both inside the chain and at the end of the chain; that is, both at the junction point and also at the terminal end. It is also possible that two or more substitutions are in an adjacent position, one with respect to the other, within the chain, provided that it results in a chemically stable compound.

Unless otherwise specified, if the substitution or interruption takes place at the terminal end, the replacement atom is attached to an H of the terminal end. For example, if -CH2CH2CH3 were optionally interrupted with -O-, the resulting compound could be -OCH2CH3, -CH2OCH3 or -CH2CH2OH.

Unless otherwise indicated, the structures shown herein also include all forms of isomeric structure (eg, enantiomeric, diastereomeric and geometric (or conformational)); for example, the R and S configurations of each asymmetric center, double bond isomers (Z) and (E) and conformational isomers (Z) and (E). Thus, simple stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are also within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Additionally, unless otherwise indicated, the structures shown also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the replacement of hydrogen by deuterium or tritium, or the substitution of carbon for carbon enriched with 13C or 14C, are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

Abbreviations

The following abbreviations are used:

DMF

Dimethylformamide

DCM

Dichloromethane

Ac

Acetyl

THF

Tetrahydrofuran

DMF

Dimethylformamide

EtOAc

Ethyl acetate

DMSO

Dimethylsulfoxide

MeCN

Acetonitrile

TFA

Trifluoroacetic acid

TCA

Trichloroacetic acid

ATP

Adenosine triphosphate

NMP

N-methylpyrrolidone

m-CPBA

M-Chloroperoxybenzoic acid

NMO

N-methylmorpholine N-oxide

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

PCC

Pyridinium Chlorochromate

EtOH

Ethanol

HOBT

Hydroxybenzotriazole

Ph

Phenyl

I

Methyl

Et

Ethyl

HEPES

4- (2-Hydroxyethyl) -1-piperazinethanesulfonic acid

BSA

Bovine serum albumin

DTT

Dithiothreitol

NMR

Nuclear magnetic resonance

FTA

Thin layer chromatography

5

10

fifteen

twenty

25

30

35

40

Four. Five

HPLC

High performance liquid chromatography

CLEM

Liquid chromatography-mass spectrometry

Tr

Holding time

In another embodiment, Z is (T) n-Q.

In one embodiment, n is 1 and T is C1-3 aliphatic optionally interrupted with a presence of 0, NR5 or S. In another embodiment, n is 0.

In some embodiments, Q is C6-10 aryl, C3-10 cycloaliphatic, 5-14 membered heteroaryl or 5-14 membered heterocyclyl. In some embodiments, Q is C6-10 aryl or 5-14 membered heteroaryl. In other embodiments, Q is 6-membered aryl or 5-6-membered heteroaryl. In some embodiments, Q is 6-membered heteroaryl. In other embodiments, Q is phenyl. In some embodiments, Q is imidazopyridine.

In some embodiments, Q is substituted with 0-5 JQ groups. In some embodiments, 0-3 JQ groups; In some embodiments, 0-1 JQ groups.

In some embodiments, each JQ is independently selected from CN, halo, C1-6 alkyl, C1-4 haloalkyl, OR0, -N (R0) 2, -SR0, - (C1-6 alkyl) -OR0, - (C1 alkyl -6) -N (R0) 2, - (C1-6 alkyl) -SR0, - (U) m- (C6-10 aryl), - (U) m (5-6 membered heteroaryl), - (U ) m- (3-12-membered heterocyclyl), (U) m- (C3-10 cycloaliphatic), -C (O) OR0, -NR0COR0, -COR0, CON (R0) 2, -SO2R0 and -SO2N (R0 )2;

U is a C1-10 alkyl, in which 0-1 methylene units are replaced by -NR0, -O-or -SM is0ó1.

In other embodiments, JQ is CN, halo, C1-6 alkyl, C1-4 haloalkyl, -OR0, -N (R0) 2, -SR0, -NH- (C1-6 alkyl) (3-8 membered heterocyclyl) , -O- (C1-6 alkyl) - (3-8-membered heterocyclyl), 3-8-membered heterocyclyl, C (O) OR0, -NR0COR0, -COR0, -CON (R0) 2, -SO2R0 or - SO2N (R0) 2. In some embodiments, JQ is -N (R0) 2, OR0 or

JQ

optionally substituted 5-8 membered heterocyclyl. In some embodiments, it is -NO2. In some embodiments, said 5-8 membered heterocyclyl contains 0-2 nitrogen atoms. In some embodiments, JQ is an optionally substituted group selected from piperidinyl, piperazinyl and pyrrolidinyl.

In some embodiments, each JQ is optional and independently substituted with 0-5 RX. In other embodiments, 0-3 RX; and in other embodiments, 0-1 RX.

In some embodiments of the present invention, RX is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, halogen, NO2, CN, NH2, NH (C1 aliphatic -4), N (C1-4 aliphatic) 2, OH, O (C1-4 aliphatic), CO2H, OCF3, CF3, COCH3, - (C1-4 alkyl) 0-1-O (C1-4 alkyl), - (C1-4 alkyl) 0-1-O (C1-4 alkyl) OH, - (C1-4 alkyl) 0-1NH (C1-4 alkyl), - (C1-4 alkyl) 0-1-N ( C1-4 alkyl) 2, - (C1-4 alkyl) 0-1-NH2 and - (C1-4 alkyl) 0-1- (3-7 membered heterocyclyl).

In some embodiments, Rx is S (O) 2CH3.

Rx J0

In some embodiments, each is optional and independently substituted with 0-5; in some embodiments, 0-3 J0; in some embodiments, 0-1 J0.

In some embodiments of this invention, R0 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, COCH3, - (C1-4 alkyl) -O (alkyl C1-4), - (C1-4 alkyl) -O (C1-4 alkyl) OH, - (C1-4 alkyl) NH (C1-4 alkyl), - (C1-4 alkyl) -N (C1- alkyl 4) 2, - (C1-4 alkyl) -NH2 and - (C1-4 alkyl) 0-1- (3-7 membered heterocyclyl).

R0 J0

In some embodiments, each is optional and independently substituted with 0-5; in some embodiments, 0-3 J0; in some embodiments, 0-1 J0;

In some embodiments, each R3 and R4 is independently H. In certain embodiments, R3 and R4 are both H.

In some embodiments, R2 is a 5-8 membered monocyclyl. In other embodiments, R2 is a C3-8 cycloaliphatic. In some embodiments, R2 is a 5-6 membered aryl or heteroaryl ring. In other embodiments, R2 is a 6-membered aryl or 6-membered heteroaryl ring having 0-2 nitrogen atoms. In other embodiments, R2 is a phenyl, pyridyl, pyrazinyl or pyrimidyl ring.

In certain embodiments, R2 is optionally substituted with 0-5 JR2; in some embodiments, 0-3 JR2; in some embodiments, 0-1 JR2.

In some embodiments, JR2 is independently oxo or halo. In certain embodiments, JR2 is independently selected from C 1-6 alkyl, phenyl, -C 1-6 alkyl- (phenyl), 5-6 membered heteroaryl, -C 1-6 alkyl- (5-6 membered heteroaryl), heterocyclyl 3-8 members, -C1-6 alkyl- (3-8-membered heterocyclyl), C1-4 haloalkyl, -OR0, N (R0) 2, -SR0, NO2, CN, - (C1-6 alkyl) -OR0 , - (C1-6 alkyl) -N (R0) 2, - (C1-6 alkyl) -SR0, -C (O) OR0, -NR0COR0, -COR0, CON (R0) 2, -SO2R0, -SO2N ( R0) 2 and a C1-6 alkylidene chain in which up to three methylene units of the chain are independently replaced by -NR0, -O-, -S-, -SO-, SO2-or -CO-. In other embodiments, JR2 is selected from -OR0, -N (R0) 2, -SR0, - (C1-6 alkyl) -OR0, - (C1-6 alkyl) -N (R0) 2 or - (C1- alkyl) 6) -SR0.

In some embodiments, each JR2 is optional and independently substituted with 0-5 RX; in some embodiments, 0-3 Rx; in some embodiments, 0-1 Rx. In some embodiments, the variables are as shown in the compounds of Table 1. In one embodiment, the invention consists of the compounds shown in Table 1. Table 1

image2

General Synthetic Methodology

The compounds of the present invention can be prepared, in general, by methods such as those shown in the following schemes and in the following preparative examples.

Scheme 1

image 1

Reagents and conditions: (a) bis (pinacolato) diboro, Pd (OAc) 2, KOAc, DMF, 80 ° C; (b) R2-Hal, Pd (Pph3) 4, Na2CO3 aq., toluene, ETOH, reflux; (c) HCl aq / dioxane, reflux.

5 Scheme 1 above shows a general synthetic route that is used to prepare compounds 4 of the present invention, in which Z and R2 are as described above. The compounds of formula 4 can be prepared from intermediates 1 in which W is a fluorine atom or an alkoxy group. The compounds of formula 2 are formed by reacting bromide 1 with bis (pinacolato) diboro in the presence of palladium as a catalyst. The formation of derivatives 3 is achieved by treating the derivatives 2 of boronic ester with a halide in

The presence of palladium as a catalyst, through the use of Suzuki coupling procedures that are well known in the art. The reaction can be carried out with a variety of substituted halides R2-Hal. The unprotection of 3 in acidic conditions leads to the formation of 4.

Scheme 2

image 1

15 Reagents and conditions: (a) tBuOk, THF, 0 ° C at ta

Scheme 2 above shows a general synthetic route that is used to prepare compounds 1a (which can be used as the starting point of Scheme 1). The compounds of formula 1a can be prepared by reacting an aldehyde 5 (J. Het. Chem, 1985, (22), 1583-1592) with a phosphonate 6, in the presence of a base. The reaction can be carried out with a variety of phosphonates.

20 Scheme 3

image 1

Reagents and conditions: (a) Pd (PPh3) 4, Na2CO3 aq., Toluene, EtOH, 120 ° C.

Scheme 3 above shows a general synthetic route that is used to prepare compounds 1b (which can be used as the starting point of Scheme 1). The compounds of formula 1b can be prepared by reacting boronic acid 7 (J. Org. Chem, 2003, (68), 3352-3355) with iodoalkene 8, in the presence of palladium as a catalyst. The reaction can be carried out with a variety of substituted haloalkenes.

Scheme 4

image 1

Reagents and conditions: (a) piperidine, EtOH, 80 ° C

Scheme 4 above shows a general synthetic route that is used to prepare compounds 1c (which is

5 can be used as a starting point in Scheme 1). The compounds of formula 1c can be prepared by an aldophilic reaction between an aldehyde 5 (J. Het. Chem, 1985, (22), 1583-1592) and an active methylene moiety of compound 9 (wherein EWG is a group electron attractant), in the presence of a weak base. The reaction can be carried out with a variety of compounds that possess an active methylene moiety.

Accordingly, the present invention also provides a process for preparing the compound of the present invention.

An embodiment of the present invention provides a process for preparing a compound of formula 4:

image 1

that understands

a) reacting a compound of formula 1 with an appropriate boronic acid ester precursor under Pd coupling conditions to form a compound of formula 2;

b) coupling the compound of formula 2, in which Z is as defined herein and W is F

or alkoxy, with R2-hal, wherein R2 is as defined herein and hal is a halogen, to form a compound of formula 3:

image 1

wherein R2, W and Z are as defined herein;

c) heating the compound of formula 3 under acidic conditions to form a compound of formula 4 in which Z and R2 are as defined herein.

In some embodiments, the boronic ester is replaced by a boronic acid. The processes for preparing boronic acids and boronic acid pinacol esters are well known to those skilled in the art.

Another embodiment of the present invention provides a process for preparing the compound of formula 4:

image 1

that understands reacting a compound of formula 2;

10

image 1

wherein Z is as defined herein and W is F or alkoxy, with R2-hal, wherein R2 is as defined herein and hal is halogen, to form a compound of formula 3:

fifteen

image 1

wherein R2, W and Z are as defined herein.

Another embodiment provides a process for preparing a compound of formula 3:

image 1

wherein R2, Z and W are as defined herein;

20 comprising reacting a compound of formula 1, under appropriate conditions, with R2-hal; wherein R2 is as defined herein and hal is a halogen, to form a compound of formula 3;

image 1

in which Z and W are as defined herein;

The appropriate conditions for coupling two halo-substituted aryl groups are well known to those skilled in the art.

Pharmaceutical compositions

As described above, the present invention provides compounds that are protein kinase inhibitors, and therefore the present compounds are useful for the treatment of diseases, disorders and conditions that include, but are not limited to, autoimmune, inflammatory, proliferative or hyperproliferative diseases. or diseases with immune intervention. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, these compositions comprising any of the compounds as described herein and optionally comprising a pharmaceutically acceptable excipient, adjuvant or carrier. In certain embodiments, these compositions may optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain compounds of the present invention may exist in free form for treatment or, when appropriate, as one of their pharmaceutically acceptable derivatives. In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters or any other adduct, salt or derivative thereof, which after administration to a patient in need thereof, is capable of providing, directly or indirectly, a compound as described herein in another way, or a metabolite or remainder thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and lower animals without it Assume toxicity, irritation, allergic response and similar unwanted and corresponding to a reasonable risk / benefit ratio. A "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of the present invention that, upon administration to a receptor, is capable of providing, either directly or indirectly, a compound of the present invention or a metabolite active from the point of view of inhibition or a remainder thereof. As used herein, the term "active metabolite from the standpoint of inhibition or remainder thereof" means that a metabolite or remainder thereof is also an inhibitor of a protein kinase protein kinase family Tec (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk).

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate , heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, phenylate 3 , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts. The present invention also provides for the quaternization of any group containing basic nitrogen of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by means of said quaternization. Representative salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulphonate.

As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable excipient, adjuvant or carrier, which, as used herein, includes each and every solvent, diluent or other liquid carrier, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publising Co., Easton, Pa., 1980) discloses various vehicles used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. Except that to the extent that any conventional vehicle medium is incompatible with the compounds of the invention, such as by the production of any unwanted biological effect or otherwise negatively interacting with any other component or components of the composition pharmaceutically acceptable, it is contemplated that its use is within the scope of the present invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial mixtures of glycerides of saturated fatty acids of vegetable origin, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, anhydrous lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth in powder form; malt; jelly; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and anti- Oxidizers may also be present in the composition, according to the criteria of the person carrying out the formulation.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as powder, ointment or drops), buccally, as an oral spray or nasal, or similar, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally in dosages of from about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, by weight. body of the subject per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid pharmaceutical forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, micro-emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid pharmaceutical forms may contain inert diluents commonly used in the art such as, for example, water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oils, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acid and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfumes.

Injectable preparations can be formulated, for example, sterile injectable aqueous or oleaginous suspensions, according to the known technique using suitable wetting or dispersing agents and suspending agents. The injectable sterile preparation may also be a sterile injectable solution, suspension or emulsion, in a non-toxic parenterally acceptable diluent or solvent, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution,

U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvent or suspension medium. For this purpose, soft fixed oils including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable compositions.

Injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria or by the incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other medium. Sterile injection before use.

In order to prolong the effect of the compound of the present invention, it is usually desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved through the use of a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of the compound therefore depends on its dissolution rate which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, a delayed absorption of a compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable forms of delayed release are prepared by forming micro-encapsulated matrices of the biodegradable polymer compound such as polylactide-polyglycolide. Depending on the proportion of the compound with respect to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable delayed release formulations are also prepared by trapping the compound in liposomes or micro-emulsions that are compatible with body tissues.

Preferably, compositions for rectal or vaginal administration are suppositories that can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or suppository wax that are solid at room temperature but liquid at body temperature. and therefore they melt in the rectum or vaginal cavity and release the active compound.

Solid pharmaceutical forms for oral administration include capsules, tablets, pills, powders and granules. In said solid pharmaceutical forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier or excipient such as sodium citrate or dicalcium phosphate and / or) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid , b) binders such as, for example, carboxymethyl cellulose, alginates; gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerol, d) disintegrating agents such as agaragar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of similar type can also be employed as fillers in hard or soft filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid pharmaceutical forms of tablets, dragees, capsules, pills and granules can be prepared with coatings or coatings such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition that only releases the active principle or principles or, preferably, in a particular part of the intestinal tract, optionally, in a delayed manner. Examples of interleaving compositions that can be used include polymeric substances and waxes. Solid compositions of similar type can also be employed as fillers in hard or soft filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be found in micro-encapsulated form with one or more excipients as discussed above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In said solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, tablet-forming lubricants and other tablet-forming aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Optionally, they may contain opacity agents and may be of a composition that releases only the active principle or principles or, preferably, in a particular part of the intestinal tract, optionally, in a delayed manner. Examples of interleaving compositions that can be used include polymeric substances and waxes.

Pharmaceutical forms for topical or transdermal administration of the compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any necessary preservative or buffer as required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of trans-dermal patches, which have the added advantage of providing a controlled contribution of the compound to the organism. Said dosage forms can be prepared by dissolving or supplying the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The velocity can be controlled either by providing a velocity control membrane or by dispersing the compound in a polymer matrix or gel.

Treatment procedures

As described above in general, the compounds of the present invention are useful as protein kinase inhibitors. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of the Tec family kinases (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) and therefore, the compounds and the compositions are particularly useful for the treatment or attenuation of the severity of a disease, condition or disorder when the activation of one or more kinases of the Tec family is involved (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) in the disease, condition or disorder. When the activation of the Tec family (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) is involved in a particular disease, condition or disorder, the disease, condition or disorder can also be referred to as "mediated disease by the Tec family (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) ”or disease symptom.

Accordingly, in another aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for treating or attenuating the severity of a disease, condition or disorder in which the activation of one or more of the family Tec (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) is involved in the disease state.

In some embodiments, said Tec family-mediated disease is a Itk-mediated disease. In certain embodiments of the present invention, an "effective amount" of the pharmaceutically acceptable compound or composition is the amount effective for the disease mediated by the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk). The compounds and compositions can be administered using any amount and any effective route of administration for the treatment or attenuation of the severity of the disease mediated by the Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk).

The exact amount required will vary from one subject to another, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration and the like. Preferably, the compounds of the invention are formulated in a unit dosage form for reasons of ease of administration and dosage uniformity. The term "unit dosage form", as used herein, refers to a physically discrete unit of an agent appropriate for the patient to be treated. However, it should be understood that the total daily use of the compounds and compositions of the present invention will be decided in accordance with the physician in charge within the scope of the sensible medical criteria. The specific effective dose level for any particular patient or organism depends on a variety of factors that include the disorder to be treated and the severity thereof; the activity of the specific compound employed; the specific composition used; the age, body weight, general health, sex and diet of the patient; the administration time, administration route and excretion rate of the specific compound employed; the duration of treatment; medicines used in combination or in a manner consistent with the specific compound employed and similar factors well known in medical techniques. The term "patient," as used herein, means an animal, preferably a mammal, and more preferably a human being.

The term "tyrosine kinase mediated condition of the Tec family", as used herein means any disease or other adverse condition in which it is known that the kinase of the Tec family play a role. Such conditions include, without limitation, autoimmune, inflammatory, proliferative and hyperproliferative diseases and diseases with immunological intervention including rejection of transplanted organs or tissues and Acquired Immune Deficiency Syndrome (AIDS).

For example, tyrosine kinase mediated conditions of the Tec family include respiratory tract diseases including, without limitation, obstructive diseases of the reversible airways that include asthma, such as bronchial, allergic, intrinsic, extrinsic and dust-induced asthma, particularly inveterate or chronic asthma (for example, hyper-reactivity of the respiratory tract against late asthma) and bronchitis. Additionally, tyrosine kinase diseases of the Tec family include, without limitation, conditions characterized by inflammation of the nasal mucosa membrane, including acute rhinitis, atrophic rhinitis, allergy and chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and medicated rhinitis; Membranous rhinitis including crupose, fibrinous and pseudomembranous rhinitis and scrofulous rhinitis, seasonal rhinitis including nerve rhinitis (pollinic rhinitis) and vasomotor rhinitis, sarcoidoysis, peasant's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia.

Tyrosine kinase-mediated conditions of the Tec family also include bone and joint diseases that include, without limitation, (synovial cloth formation in) rheumatic arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), disease of Behcet, Sjogren's syndrome and generalized sclerosis.

Kinase-mediated conditions of the Tec family also include skin diseases and disorders, including, without limitation, psoriasis, generalized sclerosis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, vesicular pemphigus, bullous epidermolysis, urticaria, angioderma, vasculitis, erythema, cutaneous eosinophilias, uveitis, alopecia areata and spring conjunctivitis.

Tyrosine kinase-mediated conditions of the Tec family also include diseases and disorders of the gastrointestinal tract including, without limitation, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies that have remote effects from the intestine, for example, migraine, rhinitis and eczema.

Tyrosine kinase-mediated conditions of the Tec family also include diseases and disorders of other tissues and multi-organic diseases including, without limitation, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, disseminated lupus erythematosus, thyroiditis Hashimoto, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper IgE syndrome, lepromatous leprosy, Sezary lymphoma and idiopathic thrombocytopenic purpura, post-angioplasty restenosis, tumors (eg leukemia and lymphomas), arteriosclerosis and lupus erythematosus disseminated.

Tyrosine kinase mediated conditions of the Tec family also include allograft rejection including, without limitation, acute and chronic allograft rejection after, for example, kidney, heart, liver, lung, bone marrow, skin and cornea transplantation; and graft versus host disease.

Combination therapies

It will also be appreciated that the pharmaceutically acceptable compounds and compositions of the present invention can be employed in combination therapies, that is, the pharmaceutically acceptable compounds and compositions can be administered simultaneously with, before, or after, one or more procedures. additional therapeutic or desired physicians. The particular combination of therapies (therapeutic products or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic products and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed can achieve a desired effect to treat the same disorder (for example, the compound of the invention can be administered simultaneously with another agent used to treat the same disorder) or can achieve different effects (for example , control of any harmful effects). As used herein, additional therapeutic agents that are normally administered to treat

or avoid a particular disease or condition, they are known as "appropriate for the disease or condition, object of treatment".

For example, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, for example, other therapies or anticancer agents that can be used in combination with the anti-cancer agents of the invention include surgery, radiotherapy (in most examples, gamma radiation, radiotherapy neutron beam, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioactive isotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, attenuating agents for harmful effects (for example, anti-emetics) and other approved chemotherapeutic drugs that include, but are not limited to, alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, Ifosfamide), antimetabolites (methotrexate), antagonists of purine and pyrimidine antagonists (6-mercaptopurine, 5-f luorouracil, cytarabine, gemcitabine), fusiform toxins (vinblastine, vincristine, vinorrelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan and topotecan), antibiotics (doxorubicin, bleomycin and mitomycin), nitrosoureas (carmustine, cisomtin, carbomoplatin, lominetin, caromustine, cisomtinoin, carbomoplatin, lominetin, carbomoplatin, lominetin, carbomoplatin, lominetin, carbomoplatin, lominetin, carbomoplatin, cisomtin, carbominolatin ), enzymes (asparaginase) and hormones (tamoxifen, leuprolide, flutamide and megestrol), GleevecTM, adriamycin, dexamethasone and cyclophosphamide. For a more complete analysis of current cancer therapies, see http://www.nci.nih.gov/, a list of FDA-approved cancer medications at http://www.fda.gov/cder/cancer/ druglistframe.htm, and The Merck Manual, 17th ed., 1999.

Other examples of agents with which the inhibitors of the present invention can be combined include, without limitation: treatments for Alzheimer's disease such as Aricept® and Excelon®; treatments for Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinrol, pramipexole, bromocriptine, pergolide, trihexefendyl and amantadine; agents for the treatment of multiple sclerosis (MS) such as interferon beta (for example, Avonex® and Rebif®), Copaxone® and mitoxantrone; asthma treatments such as albuterol and Singulair®; agents for the treatment of schizophrenia such as zyprexa, risperidone, seroquel and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blocking agents, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immuno-modulating and immuno-suppressing agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotropic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsant agents, ionic channel blocking agents, riluzole, anti-Parkinson's agents; agents for the treatment of cardiovascular diseases such as beta blocking agents, ACE inhibitors, diuretics, nitrates, calcium channel blocking agents and statins; agents for the treatment of liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders such as corticosteroids, anti-leukemic agents and developmental factors; and agents for the treatment of immunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositions of the present invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active ingredient. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active principle.

Medical devices

The compounds of the present invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described above in general, and in classes and subclasses of the present document, and a vehicle suitable for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described above in general, and in classes and subclasses of this document, and an appropriate vehicle for coating said device. implantable

Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vascular wall after injury). However, patients who use stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be avoided or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Appropriate coatings and the general preparation of coated implantable devices are described in US Pat. 6,099,562; 5,886,026 and 5,304,121. Typically, the coatings are bio-compatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. Optionally, the coatings may also be covered by an appropriate top coat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to confer on the composition controlled release characteristics.

In vitro uses

The activity of a compound used in the present invention as a kinase inhibitor of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) can be tested in vitro, in vivo or in a Cellphone line. In vitro assays include assays that determine the inhibition of either the phosphorylation activity or the activity of the activated kinase ATPase of the Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk ). Alternative in vitro assays quantify the ability of the inhibitor to bind to a kinase of the Tec family (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk). The inhibitor binding can be measured by radiolabeling of the inhibitor before binding, isolation of the inhibitor / Tec family complex (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) and quantity determination radio and marker attached. Alternatively, inhibitor binding can be determined by conducting a competition experiment in which new inhibitors are incubated with a Tec family kinase (e.g., Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) bound to known radioligands.

The term "measurable inhibit", as used herein, means a measurable change in the activity of a kinase of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk ) between a sample comprising said composition and a kinase of the Tec family (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) and an equivalent sample comprising a kinase of the Tec family (for example , Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) in the absence of said composition.

Biological sample

Another aspect of the invention relates to the in vitro inhibition of protein kinase activity in a biological sample, said method comprising contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample", as used herein, means an in vitro or ex vivo sample and includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extract thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. In some embodiments, said protein kinase is a kinase of the Tec family (eg, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk).

Inhibition of the kinase activity of the Tec family (for example, Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) in a biological sample is useful for a variety of purposes that are known to those skilled in the art. The matter. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological species and biological tests.

The compounds of the present invention can be prepared in general by methods known to those skilled in the art for analogous compounds or by the procedures described in the following Examples.

Examples

Example 1

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1- (4 - ((E) -2-iodovinyl) phenyl) piperidine

1- (4-ethynylphenyl) piperidine (3.49 g, 18.8 mmol) in dry THF (100 ml) was added to a suspension of bis (cyclopentadienyl) zirconium (IV) chloride hydride (5.09 g, 19 , 76 mmol) in THF (50 ml) at rt under a nitrogen atmosphere in darkness. After 1 h, iodine (3.65 g, 23.7 mmol) was added. After an additional 2 h, a saturated aqueous solution of sodium sulphite (50 ml) was added carefully and the reaction mixture was partitioned between water (30 ml) and EtOAc (100 ml). The organic phase was separated, dried (MgSO4), filtered and concentrated. Purification by column chromatography (5% EtOAc in EP) resulted in the title compound (3.08 g, 52%) as a colorless solid. 1H NMR (CDCl3) 1.61 (2H, m), 1.70 (4H, m), 3.20 (4H, m), 6.54 (1H, d), 6.83 (2H, d), 7.19 (2H, d), 7.31 (1H, d).

15 Procedure 2

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3- (4- (Piperidin-1-yl) styryl) -5-bromo-2-fluoropyridine

To a solution of 1- (4 - ((E) -2-iodovinyl) phenyl) piperidine (687 mg, 2.19 mmol) and 5-bromo-2-methoxypyridin-3-yl-3boronic acid (578 mg, 2 , 63 mmol) in EtOH (8 ml) and toluene (36 ml) sodium carbonate (627 mg, 5.92 mmol) in water (18 ml) was added. Nitrogen was bubbled through the reaction mixture for 40 minutes and then tetrakis (triphenylphosphine) palladium (127 mg, 0.11 mmol) was added to the refluxed mixture for 15 minutes. EtOAc (50 ml) and water (20 ml) were added, and after extraction, the organic phase was dried (MgSO4), filtered and concentrated. Purification by column chromatography (5% EtOAc in EP) gave the title compound (198 mg, 25%) as a yellow solid. 1H NMR (CDCl3) 1.62 (2H, m), 1.70 (4H, m), 3.28 (4H, m), 6.87 (1H, d),

25 6.91 (2H, d), 7.15 (1H, d), 7.43 (2H, d), 8.08 (2H, d).

Procedure 3

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3- (4- (Piperidin-1-yl) styryl) -2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine

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A 50 ml flask was charged with 3- (4- (piperidin-1-yl) styryl) -5-bromo-2-fluoropyridine (521 mg, 1.44 mmol), KOAc (428 mg, 4.36 mmol) , bis (pinacolato) diboro (403 mg, 1.59 mmol) and PdCl2 (dppf) (30 mg, 42.7 µmol) in a nitrogen atmosphere. Anhydrous dioxane (30 ml) was added and the reaction mixture was heated at 120 ° C for 16 h. EtOAc (30 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried (MgSO4), filtered and concentrated and the residue was purified by column chromatography (15% to 50% EtOAc in EP), to give the title compound (435 mg, 83%) as solid yellow.

Procedure 4

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3- (4- (Piperidin-1-yl) styryl) -5- (2- (methylamino) pyrimidin-4-yl) pyridin-2 (1H) -one. I.2

A 100 ml round bottom flask was charged with 3- (4- (piperidin-1-yl) styryl) -2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2 -yl) pyridine (199 mg, 0.49 mmol), 4-chloro-N-methylpyrimidin-2-amine (146 mg, 1,016 mmol) and Pd (PPh3) 4 (59 mg, 50.9 µmol). Then, toluene (20 ml), EtOH (10 ml) and aq K2CO3 were added. 2 M (1.53 ml, 3.05 mmol) and the reaction mixture was immersed in an oil bath at 120 ° C for 1 h. The reaction mixture was partitioned between EtOAc (30 ml) and water (50 ml), and the organic phase was dried (MgSO4), filtered, concentrated and then filtered on silica (MeOH / CH2Cl2 gradient). After evaporation of the volatiles, the residue was dissolved in dioxane (8 ml) and water (3 ml), and concentrated HCl (0.66 ml) was added. The reaction mixture was heated at 110 ° C for 70 min and then evaporated. Purification by preparative reverse phase HPLC (eluting with TFA aq / MeCN) gave the title compound (40 mg, 21%) as a yellow solid.

Example 2

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Tert-butyl 4- (4- (hydroxymethyl) phenyl) piperazin-1-carboxylate

4- (4- (tert-Butoxycarbonyl) piperazin-1-yl) benzoic acid (10 g, 32.64 mmol) was dissolved in anhydrous THF (200 ml) under a nitrogen atmosphere at 0 ° C and BH3 THF ( 1 M in THF, 65.3 ml, 65.3 mmol) for 15 minutes. The reaction was maintained at this temperature and after 3 h another portion of BH3 THF (1 M in THF, 10 ml, 10 mmol) was added. After 2 h, MeOH (30 ml) was added and the reaction was heated to rt. The reaction mixture was partitioned between EtOAc (150 ml) and brine (200 ml). The aqueous phase was extracted again with EtOAc (100 ml) and the combined organic products were washed with a saturated aqueous solution of NaHCO3 (150 ml) and then dried (MgSO4) and filtered. At the concentration of the solution, the title compound (8.57 g, 90%) precipitated as a white solid and was collected by filtration. 1H NMR (CDCl3) 1.51 (9H, s), 8.14 (4H, t), 3.62 (4H, t), 4.62 (2H, d), 6.94 (2H, d), 7.31 (2H, d).

Procedure 6

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(4- (4- (tert-Butoxycarbonyl) piperazin-1-yl) phenyl) diethyl methylphosphonate

Thionyl chloride (1 ml) was added to a solution of tert-butyl 4- (4- (hydroxymethyl) phenyl) piperazin-1-carboxylate (1.2 g, 4.10 mmol) in CH2Cl2 (45 ml). After 40 min., The reaction was concentrated. Then, triethyl phosphite (15 ml) was added and the reaction mixture was heated to 170 ° C. After 90 minutes, the reaction was concentrated and the residue was purified by column chromatography (eluting with EtOAc), to give the title compound (1.63 g, 96%) as a colorless oil.

Procedure 7

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Tert-Butyl 4- (4 - ((E) -2- (5-Bromo-2-methoxypyridin-3-yl) vinyl) phenyl) piperazin-1-carboxylate

A diethyl 5-bromo-2-methoxypyridin-3-carbaldehyde (1.5 g, 6.95 mmol) and (4- (4- (tert-butoxycarbonyl) piperazin-1yl) phenyl) methylphosphonate (2.39 g, 5.79 mmol) in anhydrous THF (50 ml) under a nitrogen atmosphere, potassium tert-butoxide (1.30 g, 11.6 mmol) was added at rt for 5 min. After 3 h, another portion of aldehyde (160 mg, 0.74 mmol) was added. After an additional 30 min, the reaction was concentrated and the residue was purified by column chromatography (30% EtOAc in EP), to give the title compound (2.27 g, 83%) as an oil of yellow color. 1H NMR (CDCl3) 1.51 (9H, s), 3.24 (4H, t), 3.68 (4H, t), 4.00 (3H, s), 7.02 (2H, d), 7.11 (2H, m), 7.49 (2H, d), 7.89 (1H, s), 8.07 (1H, s).

Procedure 8

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4- (4 - ((E) -2- (2-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) vinyl) phenyl) tert-butyl piperazin-2-carboxylate

To a mixture of tert-butyl (4- (4 - ((E) -2- (5-bromo-2-methoxypyridin-3-yl) vinyl) phenyl) piperazin-1-carboxylate (2.07 g, 4 , 36 mmol), bis (pinacolato) diboro (1.22 g, 4.80 mmol), potassium acetate (1.29 g, 13.1 mmol) and PdCl2 (dppf) (91 mg, 0.13 mmol) in An atmosphere of nitrogen was added anhydrous dioxane (60 ml) and the reaction mixture was heated at reflux overnight The reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The aqueous phase was extracted. again with EtOAc (50 ml) and the combined organic products were dried (MgSO4), filtered and concentrated.The residue was filtered through a short bed of silica (with 50% EtOAc in EP). , the title compound (1.90 g, 84%) precipitated as a white solid 1 H NMR (CDCl 3) 1.38 (12H, s), 1.50 (9H, s), 3.20 ( 4H, t), 3.63 (4H, t), 4.09 (3H, s), 6.95 (2H, d), 7.02 (2H, m), 8.17 (1H, s), 8.56 (1H, s).

Procedure 9

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Tert-Butyl 4- (4 - ((E) -2- (2-Methoxy-5- (2- (methylamino) pyrimidin-4-yl) pyridin-3-yl) phenyl) piperazin-1-carboxylate

A 4- (4 - ((E) -2- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) vinyl ) phenyl) tert-butyl piperazin-1-carboxylate (191 mg, 0.37 mmol) and 4-chloro-N-methylpyrimidin-2-amine (79 mg, 0.55 mmol) in toluene (4 ml) and ethanol (2 ml) in a nitrogen atmosphere 2M aqueous potassium carbonate was added followed by tetrakis (triphenylphosphine) palladium (17 mg, 14.6 µmol). The reaction mixture was heated at 120 ° C overnight. The reaction mixture was partitioned between EtOAc (30 ml) and water (50 ml). The organic phase was dried (MgSO4), filtered and concentrated and the residue was purified by column chromatography (EtOAc) to give the title compound (168 mg, 91%) as a yellow solid.

Procedure 10

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5 3- (4- (Piperazin-1-yl) styryl) -5- (2- (methylamino) pyrimidin-4-yl) pyridin-2- (1H) -one. I.4

Pyridine hydrochloride (2 g) was added to 4- (4 - ((E) -2- (2-methoxy-5- (2- (methylamino) pyrimidin-4-yl) pyridin-3-yl) vinyl) phenyl) piperazin -1-tert-butyl carboxylate (168 mg, 0.33 mmol) and the mixture was heated at 150 ° C for 30 minutes. The reaction mixture was dissolved in MeOH (30 ml) and solid sodium bicarbonate was added until bubbling stopped. The suspension was filtered and the filtrate was concentrated. Purification by column chromatography (gradient

DCM / MeOH / NH3) gave the title compound (122 mg, 94%) as a yellow solid.

Example 3 (Reference Example)

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3 - ((5-Bromo-2-methoxypyridin-3-yl) methylene) indolin-2-one

To a solution of indolinone (130 mg, 0.98 mmol) in ethanol (5 ml) was added 5-bromo-2-methoxypyridin-3carbaldehyde (J. Het. Chem., 1985, (22), 1583-1592) (200 mg, 0.98 mmol), 1 equiv. followed by piperidine (0.194 ml, 1.9 mmol, 2 equiv.). The reaction mixture was heated at 80 ° C for 2 hours and then allowed to cool to

20 room temperature. The precipitate that formed was collected by filtration and washed with ethanol to give the title compound (180 mg, 55%).

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3 - ((1,2-Dihydro-5- (6- (methylamino) pyrazin-2-yl) -2-oxopyridin-3-yl) methylene) indolin-2-one. I.6

It was prepared from 3 - ((5-bromo-2-methoxypyridin-3-yl) methylene) indolin-2-one using procedures similar to those described in Procedure 8-10.

A variety of other compounds of Formula I have been prepared by procedures substantially similar to those described herein in Examples 1 to 3. Characterization data for these compounds are summarized below in Table 2 and include the HPLC, LC / MS (observed) and 1H NMR data.

The 1H NMR data were summarized in Table 2 and found to be consistent with the structure. 1 H NMR spectra were recorded at 400 MHz, using a Bruker DPX 400 instrument in deuterated DMSO, unless otherwise indicated.

The CLEM samples were analyzed on a MicroMass Quattro Micro mass spectrometer that worked on

5 simple EM mode with electrospray ionization. Samples were introduced into the mass spectrometer using chromatography. The mobile phase for all mass spectrometry analyzes consisted of 10 mM ammonium acetate at pH 7 and a 1: 1 mixture of acetonitrile-methanol, the column gradient conditions were 5% -100% acetonitrile during methanol. a gradient time of 4.5 min and a development time of 6.2 min on an ACE C8 3.0 x 75 mm column. The flow rate was 1.0 ml / min. As used herein, the term

"Tr (min)" refers to the retention time of CLEM, in minutes, associated with the compound.

Compound numbers correspond to compound numbers that are listed in Table 1.

Table 2. Characterization data for the selected compounds of formula I

. compound

M + 1 (obs) Tr (min) 1H NMR

I.1

357.1 11.05 (CDCl3) 1.60-1.68 (2H, m), 1.70-1.80 (4H, m), 3.22-3.30 (4H, m), 6.98 (1H, br s ), 7.01 (2H, s), 7.22 (1H, d), 7.39 (1H, t), 7.43-7.54 (7H, m), 7.60 (1H, s) , 7.95 (1H, s)

I.2

388.2 11.05 1.52-1.65 (6H, m), 2.86 (3H, s), 3.20 (4H, t), 6.93 (2H, d), 7.00 (1H, d), 7 , 07-7.09 (2H, m), 7.39 (2H, d), 7.65 (1H, d), 8.12 (1H, s), 8.28 (1H, s), 8, 30 (1H, s)

I.3

389.4 7.09 2.89 (3H, s), 2.94 (4H, t), 3.18 (4H, t), 6.94 (2H, s), 7.09 (1H, d, 16.5 Hz), 7.11 (1H, m), 7.42 (2H, d), 7.70 (1H, d, 16.5 Hz), 7.80 (1H, s), 8.01 (1H, s), 8.22 (1H, s), 8.31 (1H, s)

I.4

389.5 7.24 2.82 (4H, t), 2.89 (3H, m), 3.10 (4H, t), 6.93 (2H, d), 7.03 (1H, d), 7.08 (2H , m), 7.42 (2H, d), 7.66 (1H, d, 16.5 Hz), 8.14 (1H, s), 8.28 (1H, m), 8.31 (1H , s)

I.5

388.4 6.93 2.79 (3H, m), 2.87-2.90 (4H, m), 3.15-3.21 (4H, m), 6.94 (2H, d), 7.03 (1H, t), 7.07 (1H, d), 7.42 (2H, d), 7.64 (1H, d), 7.71 (1H, d), 7.89 (1H, d), 8, 01 (1H, d), 8.03 (1H, d)

I.6

346.3 7.02 2.81 (3H, d), 6.89 (2H, d), 7.10-7.18 (1H, m), 7.25 (1H, t), 7.57 (1H, s), 7 , 75 (1H, d), 7.81 (1H, s), 8.20 (1H, s), 8.33 (1H, d), 8.86 (1H, d), 10.63 (1H, sa)

I.7

526 8.21 2.48-2.57 (4H, m), 2.86-2.91 (6H, m), 3.11-3.19 (4H, m), 3.69 (2H, s), 7, 10-7.16 (1H, m), 7.10 (1H, d), 7.48 (1H, dd), 7.81 (1H, s), 7.83-7.87 (1H, m) , 7.80 (1H, d), 8.14 (1H, d), 8.19 (1H, d), 8.21 (1H, s), 8.45 (1H, d), 12.25 ( 0.5H, sa)

I.8

380 8.60 2.89 (3H, d, J = 4.7 Hz), 3.75 (3H, s), 7.05 (1H, dd), 7.087.17 (1H, m), 7.28 (1H, d ), 7.34 (1H, d), 7.81 (1H, s), 8.03 (1H, d), 8.13 (1H, d), 8.19 (1H, s), 8.32 (1H, d), 8.41 (1H, d), 11.98 (0.5 H, sa)

I.9

348 3.40 7.42-7.58 (6H, m), 7.606-7.64 (1H, m), 7.85 (1H, t), 7.93 (1H, d), 8.02 (1H, d) , 8.07 (1H, d), 8.55 (1H, s), 9.01 (1H, d), 12.23 (1H, sa)

Example 4: Itk inhibition assay

The compounds of the present invention can be evaluated as inhibitors of human Itk kinase using either a radioactivity based assay or a spectrophotometric assay. In general, the compounds of the invention, including the compounds of Table 1, are effective for Itk inhibition. Specifically, compounds I.1 to I.5 and compound I.7 have a value of Ki <1 µM and compounds of 1.6 and 1.8 have a value of Ki> 1 µM.

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Itk inhibition assay: Radioactivity based assay

The tests were carried out in a mixture of 100 mM HEPES (pH 7.5), 10 mM MgCl2, 25 mM NaCl, 0.01% BSA and 1 mM DTT. Final substrate concentrations were 15 µM [γ-33P] ATP (400 µCi 33P ATP / µmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 2 µM peptide (SAM68 protein 32332-443). The tests were carried out at 25 ° C in the presence of 30 nM Itk. A stock buffer solution was prepared containing all the reagents listed above, except for ATP and the test compound of interest. 50 µl of stock solution was introduced into a 96-well plate followed by the addition of 1.5 µl of serial dilutions of the test compound containing mother DMSO (typically starting from a final concentration of 15 µM with serial dilutions 2 times) in duplicate (final concentration of DMSO 1.5%). The plate was pre-incubated for 10 minutes at 25 ° C and the reaction was initiated by adding 50 µl of [γ-33P] ATP (final concentration of 15 µM).

The reaction was stopped after 10 minutes by adding 50 µl of a TCA / ATP mixture (20% TCA, 0.4 mM ATP). A 96-well GF / C Unifilter plate (Perkin Elmer Life Sciences, Cat. No. 6005174) was pre-treated with 50 µl of Mili Q water before the addition of the entire reaction mixture (150 µl). The plate was washed with 200 µl of Mili Q water followed by 200 µl of a mixture of TCA / ATP (5% TCA, 1 mM ATP). This wash cycle was repeated another 2 times. After drying, 30 µl of Optiphase "SuperMix" liquid scintillation cocktail (Perkin Elmer) was added to the well before scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

The IC50 data was calculated from nonlinear regression analysis of the initial rate data using a Prism software package (GraphPad Prism version 3.0 cx for Macintosh, GraphPad Software, San Diego, California, USA). ). The tests were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl2, 0.1% BSA and 1mM DTT. The final substrate concentrations in the assay were [γ-33P] 7.5 µM ATP (400 µCi 33P ATP / µmol ATP, Amersham Pharmacia Biotech / Sigma Chemicals) and 3 µM peptide (SAM68 protein ∆1332443). The tests were carried out at 25 ° C in the presence of 50 nM Itk. A stock buffer solution was prepared containing all the reagents listed above, except for ATP and the test compound of interest. 50 µl of the stock solution was introduced into a 96-well plate followed by the addition of 2 µl of serial dilutions of the test compound containing mother DMSO (typically starting from a final concentration of 50 µM with serial dilutions 2 times) in duplicate (final concentration of DMSO 2%). The plate was pre-incubated for 10 minutes at 25 ° C and the reaction was initiated by the addition of 50 µl of [γ-33P] ATP (final concentration of 7.5 µM).

The reaction was stopped after 10 minutes by the addition of 100 µl of 0.2 M phosphoric acid + 0.01% TWEEN 20. A 96-well multi-screen phosphocellulose filter plate (Millipore, Cat No. MAPHNOB50) was pre-treated with 100 µl of 0.2 M phosphoric acid + 0.01% TWEEN 20 before the addition of 170 µl of the test mixture whose reaction had stopped. The plate was washed with 4 x 200 µl of 0.2 M phosphoric acid

+ TWEEN 20 0.01%. After drying, 30 µl of Optiphase "SuperMix" liquid scintillation cocktail (Perkin Elmer) was added to the well before scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

Ki (app) data were calculated from nonlinear regression analysis of the initial rate data using a Prism software package (GraphPad Prism version 3.0 cx for Macintosh, GraphPad Software, San Diego, California, USA). .UU.)

Itk inhibition test: Spectrophotometric test

The compounds can be explored for their ability to inhibit Itk using a conventional coupled enzyme assay (Fox et al., Protein. Sci., (1998) 7, 2249).

The tests were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl2, 0.1% BSA, 1 mM DTT, 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 µg / ml pyruvate kinase and lactate dehydrogenase 10 µg / ml. The final substrate concentrations in the assay were 100 µM ATP (Sigma Chemicals) and 3 µM peptide (biotinylated SAM68 32332-443). The tests were carried out at 25 ° C and in the presence of 100 nM Itk.

A stock buffer solution was prepared containing all the reagents listed above, except for ATP and the test compound of interest. 60 µl of stock solution was placed in a 96-well plate followed by the addition of 2 µl of serial dilutions of the test compound containing mother DMSO (typically starting with a final concentration of 15 µm). The plate was pre-incubated for 10 minutes at 25 ° C and the reaction was started by adding 5 µl of ATP. Initial reaction rates were determined with a Molecular Devices SepectraMax Plus plate reader for a period of 10 minutes. The IC50 and Ki data were calculated by means of non-linear regression analysis using the Prism software package (GraphPad Prism version 3.0 cx for Macintosh, GraphPad Software, San Diego, California, USA).

Example 5: Btk inhibition assay

Btk inhibition assay: Radioactivity based assay

The tests were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl 2, 0.1% BSA and 1 mM DTT. The final substrate concentrations in the assay were 50 µM [γ-33P] ATP (200 µCi 33P ATO / µmol ATP, Amersham Pharmacia Biotech, Amersham, UK / Sigma Chemicals) and 2 µM peptide (SAM68 32332-443). The tests were carried out at 25 ° C and in the presence of 25 nM Btk. A stock buffer solution was prepared containing all the reagents listed above, except for the peptide and the test compound of interest. 75 µl of stock solution was introduced into a 96-well plate followed by the addition of 2 µl of serial dilutions of the compound of interest containing mother DMSO (typically starting from a final concentration of 15 µM) in duplicate (final DMSO concentration of 2 %). The plate was pre-incubated for 15 minutes at 25 ° C and the reaction was initiated by the addition of 25 µl of peptide (final concentration of 2 µM). Background counts were determined by adding 100 µl of 0.2 M phosphoric acid + 0.01% TWEEN to control wells containing test buffer and DMSO before initiation with the peptide.

The reaction was stopped after 10 minutes by the addition of 100 µl of 0.2 M phosphoric acid + 0.01% TWEEN. A 96-well multi-screen phosphocellulose filter plate (Millipore, Cat No. MAPHNOB50) with 100 µl of 0.2 M phosphoric acid + 0.01% TWEEN 20 was pre-treated before the addition of 170 µl of the test mixture in which the reaction had stopped. The plate was washed with 4 x 200 µl of 0.2 M phosphoric acid + 0.01% TWEEN 20. After drying, 30 µl of an Optiphase "SuperMix" liquid scintillation cocktail (Perkin Elmer) was added to the well before scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing the average background values for all data points, Ki (app) data were calculated from nonlinear regression analysis using a Prism software package (GraphPad Prism version 3.0 cx for Macintosh, GraphPad Software, San Diego, California, USA)

Example 6: RLK inhibition assay

The ability of the compounds to inhibit Rlk was recorded using a conventional coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). The tests were carried out in a mixture of 20 mM MOPS (pH 7.0), 10 mM MgCl2, 0.1% BSA and 1mM DTT. The final substrate concentrations in the assay were 100 µM ATP (Sigma Chemicals) and 10 µM peptide (Poly Glu: Tyr 4: 1). The tests were carried out at 30 ° C and in the presence of 40 nM Rlk. The final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 µM NADH, 30 µg / ml pyruvate kinase and 10 µg / ml lactate dehydrogenase.

A stock buffer solution was prepared containing all the reagents listed above, except for ATP and the test compound of interest. 60 µl of stock solution was introduced into a 96-well plate followed by the addition of 2 µl of serial dilutions of the test compound containing mother DMSO (typically starting from a final concentration of 7.5 µM). The plate was pre-incubated for 10 minutes at 30 ° C and the reaction was initiated by the addition of 5 µl of ATP. The initial reaction rates were determined with a Molecular Devices SpectraMax Plus plate reader for a time of 10 minutes. The IC50 and Ki data values were calculated from nonlinear regression analysis using a Prism software package (GraphPad Prism version 3.0 cx for Macintosh, GraphPad Software, San Diego, California, USA).

Example 7:

Compound I.9 was tested in assays similar to those described herein and found to inhibit FLT-3, JAK2 and JAK3 kinases.

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fifty

Claims (28)

1. A compound of formula I: image 1 Formula I or a pharmaceutically acceptable salt thereof, wherein R2 is a 6-membered aryl ring or a 6-membered heteroaryl ring having 0-2 nitrogen atoms, said ring being optionally substituted with up to five JR2; each R3 and R4 is independently H, halogen or C1-4 aliphatic optionally substituted with 0-5 presence of halogen, OH, OCH3, OCF3, NO2, NH2, CN, NHCH3, SCH3, N (CH3) 2 or C1-2 aliphatic optionally substituted 0-5 times with F; You see image 1 or; wherein V is optionally and independently substituted with 0-2 presence of halogen, C1-2 aliphatic, C1-2 haloaliphatic, OH, OCH3, OCF3 or CN. R is H or C1-6 unsubstituted aliphatic; R1 is independently H, halogen, CN, NO2 or C1-4 aliphatic optionally substituted with 0-4 presence of halogen, C1-2 aliphatic, CF3, OH, OCH3, OCF3, NO2, NH2, CN, NHCH3, SCH3 or N ( CH3) 2; Z is (T) n-Q; T is a C1-6 aliphatic chain, in which up to three methylene units of the chain are optionally and independently replaced by -NR5-, -O-, -S-, -SO-, -SO2-, -CS-o -CO-; T is optionally substituted with 0-3 JT; Q is a 3-8 membered, saturated, partially unsaturated or completely unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; or is a bicyclic ring system, 8-12 members, saturated, partially unsaturated or completely unsaturated having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; Q is optionally substituted with 0-5 JQ; n is 0 or 1; R5 is H, C1-6 aliphatic, C3-6 cycloaliphatic, phenyl, benzyl, CO (C1-4 aliphatic) or -SO2 (C1-6 aliphatic), each R5 being optionally substituted with 0-5 JR5 groups; each of JT and JR5 is independently H, C3-6 cycloaliphatic, C1-6 aliphatic, halogen, NO2, CN, -NH2, NH (C1-4 aliphatic), -N (C1-4 aliphatic) 2, -OH, -O (C1-4 aliphatic), -CO2H, -CO2 (C1-4 aliphatic), -O (C1-4 haloaliphatic) or halo (C1-4 aliphatic); each of JR2 and JQ is independently halogen, -NO2, -CN, U, - (U) m- (C6-10 aryl), - (U) m- (5-12 membered heteroaryl), - (U) m- (3-12-membered heterocyclyl), - (U) m- (C3-10 cycloaliphatic), -OR0, -SR0, -N (R0) 2, - (C1-6 alkyl) -OR0, - (alkyl C1-6) -N (R0) 2, - (C1-6 alkyl) -SR0, -NR0C (O) R0, NR0C (S) R0, -NR0C (O) N (R0) 2, -NR0C (S) N (R0) 2, NR0CO2R0, NR0NR0C (O) R0, -NR0NR0C (O) N (R0) 2, -NR0NR0CO2R0, -C (O) C (O) R0, -C (O) CH2C (O) R0, -CO2R0, -C (O) R0, -C (S) R0, C (O) N (R0) 2, -C (S) N (R0) 2, -OC (O) N (R0) 2, - OC (O) R0, -C (O) N (OR0) R0, -C (NOR0) R0, -S (O) 2R0, -S (O) 3R0, -SO2N (R0) 2, S (O) R0 , -NR0SO2N (R0) 2, -NR0SO2R0, -N (OR0) R0, -C (= NH) -N (R0) 2, -P (O) 2R0, -PO (R0) 2, -OPO (R0) 2, = O, = S, = NHHR0, = NN (R0) 2, = NNHC (O) R0, = NNHCO2 (C1-6 alkyl), = NNHSO2 (C1-6 alkyl), = NOH or = NR0; each JR2 and JQ being optional and independently substituted with 0-5 RX; U is a C1-10 alkylidene chain, in which up to three methylene units of the chain are independently replaced by -NR0, -O-, -S-, -SO-, SO2-or -CO-; m is 0 or 1 each Rx is independently halogen, NO2, CN, NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, OH, O (C1-4 aliphatic), O (C1-4 haloaliphatic) , CO (C1-4 aliphatic), CO2H, CO2 (C1-4 aliphatic), C1-6 aliphatic, C1-4 haloaliphatic, phenyl, -O (Ph), 5-6 membered heteroaryl, C3-8 cycloaliphatic, heterocyclyl 5-8-member, -C1-6- (Ph) aliphatic -C 1-6 alkyl (5-6-membered heteroaryl), -C 1-6 alkyl- (C3-8 cycloaliphatic), -C1-8- alkyl 5-8-membered heterocyclyl) or a C1-10 alkylidene chain in which up to 2 methylene units of the chain are optionally substituted by O, N or S; each Rx being optional and independently substituted with 0-5 J0; each R0 is independently H, C1-6 aliphatic, C1-4 haloaliphatic, CO (C1-4 aliphatic), CO2 (C1-4 aliphatic), -SO2 (C1-4 aliphatic), -SO2 (phenyl), phenyl, heteroaryl 5-6 members, 5-6 members heterocyclyl, C3-8 cycloaliphatic, C1-6 aliphatic 5 fifteen 25 35 Four. Five (Ph), -C 1-6 alkyl- (5-6 membered heteroaryl), -C 1-6 alkyl- (5-8 membered heterocyclyl), -C 1-6 alkyl- (C 3-8 cycloaliphatic); or a C1-10 alkylidene chain in which up to 2 methylene units of the chain are optionally replaced by O, N or S; said R0 being optionally substituted with 0-5 J0; or two R0, on the same substituent or on different substituents, taken together with the atom or atoms to which each R0 is attached, form a 3-8 membered monocyclic or bicyclic ring, saturated, partially unsaturated or completely unsaturated, which it has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally and independently substituted with 0-4 presence of halogen, NO2, CN, C1-4 aliphatic, NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, OH, O (C1- aliphatic 4), CO2H, CO2 (C1-4 aliphatic), O (C1-4 haloaliphatic) or C1-4 haloaliphatic, in which each of the C1-4 aliphatic groups of R0 is unsubstituted; Each J0 is independently halogen, NO2, CN, C1-4 aliphatic, -NH2, -NH (C1-4 aliphatic), -N, O (C1-4 aliphatic), -CO2H , -CO2 (C1-4 aliphatic), -O (C1-4 haloaliphatic) or halo (C1-4 aliphatic), in which each of the C1-4 aliphatic groups is unsubstituted.

2.

The compound according to claim 1, wherein n is 1 and T is C1-3 aliphatic optionally interrupted with a presence of O, NR5 or S.

3.

The compound according to claim 1, wherein n is 0.

Four.

The compound according to any one of claims 1-3, wherein Q is C6-10 aryl, C3-10 cycloaliphatic, 5-14 membered heteroaryl or 5-14 membered heterocyclyl.

5.

The compound according to claim 4, wherein Q is C6-10 aryl or 5-14 membered heteroaryl.

6.

The compound according to claim 5, wherein Q is a 6-membered aryl or a 5-6 membered heteroaryl.

7.

The compound according to claim 6, wherein Q is a 6-membered heteroaryl.

8.

The compound according to claim 6, wherein Q is phenyl.

9.

The compound according to any one of claims 1-8, wherein Q is substituted with up to 3 JQ groups; wherein each JQ is independently selected from CN, halo, C1-6 alkyl, C1-4 haloalkyl, -OR0, - (R0) 2, -SR0, - (C1-6 alkyl) -OR0, - (C1- alkyl 6) -N (R0) 2, - (C1-6 alkyl) -SR0, - (U) m- (C610 aryl), - (U) m- (5-12 membered heteroaryl), - (U) m - (3-12 heterocyclyl), - (U) m- (C3-10 cycloaliphatic), C (O) OR0, -NR0COR0, -COR0, -CON (R0) 2, -SO2R0 and -SO2N (R0) 2; U is a C1-10 alkyl, in which 0-1 methylene units are independently replaced by -NR0, -, -O- or S-; m is 0 or 1.

10.

The compound according to claim 9, wherein each JQ is CN, halo, C1-6 alkyl, C1-4 haloalkyl, OR0, -N (R0) 2, SR0, -NH- (C1-6 alkyl) - (3-8 membered heterocyclyl), -O- (C1-C6 alkyl) - (3-8 membered heterocyclyl), 3-8 membered heterocyclyl, -C (O) OR0, NR0COR0, -COR0, -CON ( R0) 2, -SO2R0 or -SON (R0) 2, each JQ being optional and independently substituted with 0-5 RX.

eleven.

The compound according to claim 10, wherein JQ is -N (R0) 2, OR0 or a 5-8 membered heterocyclyl optionally substituted with 0-5 RX.

12.

The compound according to claim 11, wherein JQ is a group selected from piperidinyl, piperazinyl and pyrrolidinyl, said group being optionally substituted with 0-5 RX.

13.

The compound according to any one of claims 1-12, wherein RX is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, halogen, NO2 , CN, NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, OH, O (C1-4 aliphatic), CO2H, OCF3, CF3, COCH3, - (C1-4 alkyl) 0-1 -O (C1-4 alkyl), - (C1-4 alkyl) 0-1O (C1-4 alkyl) OH, - (C1-4 alkyl) 0-1-NH (C1-4 alkyl), - (C1 alkyl -4) 0-1-N (C1-4 alkyl) 2, - (C1-4 alkyl) 0-1-NH2 and - (C1-4 alkyl) 0-1 (3-7 membered heterocyclyl).

14.

The compound according to any one of claims 1-12, wherein R0 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, COCH3, - (C1-4 alkyl) -O (C1-4 alkyl), (C1-4 alkyl) -O (C1-4 alkyl) OH, - (C1-4 alkyl) -NH (C1-4 alkyl), - (alkyl C1-4) -N (C1-4 alkyl) 2, - (C1-4 alkyl) -NH2 and (C1-4 alkyl) 0-1- (3-7 membered heterocyclyl).

fifteen.

The compound according to any one of claims 1-14, wherein each R3 and R4 is independently H.

16.

The compound according to any one of claims 1-14, wherein each R3 and R4 are both H.

17.

The compound according to claim 1, wherein R2 is a phenyl, pyridyl, pyrazinyl or pyrimidyl ring, said ring being optionally substituted with up to five JR2.

JR2

18.

The compound according to any one of claims 1-17, wherein each is independently oxo or halo.

19.

The compound according to any one of claims 1-17, wherein each JR2 is independently selected from C1-6 alkyl, phenyl, -C 1-6 alkyl- (phenyl), 5-6 membered heteroaryl, -C1 alkyl -6- (heteroaryl

5 of 5-6 members), 3-8 membered heterocyclyl, -C 1-6 alkyl- (3-8 membered heterocyclyl), C1-4 haloalkyl, -OR0, N (R0) 2, SR0, NO2, CN, - (C1-6 alkyl) -OR0, - (C1-6 alkyl) -N (R0) 2, - (C1-6 alkyl) -SR0, -C (O) R0, -NR0COR0, -COR0, CON (R0 ) 2, -SO2R0, -SO2N (R0) 2 and a C1-6 alkylidene chain in which up to three methylene units in the chain are independently replaced by -NR0, -O-, -S-, -SO-, SO2-or -CO-; each JR2 being optional and independently substituted with 0-5 RX. The compound according to claim 19, wherein each JR2 is selected from -OR0, -N (R0) 2, -SR0, (C1-6 alkyl) -OR0, - (C1-6 alkyl) - N (R0) 2 or (C1-6 alkyl) -SR0; each JR2 being optional and independently substituted with 0-5 RX.

twenty-one.

The compound according to claim 1 selected from the following:

22

The compound according to claim 1 selected from the following:

2. 3.

A composition comprising a compound of any one of claims 1-22 and a pharmaceutically acceptable carrier, adjuvant or carrier.

image2 image 1 A method in vitro for inhibiting protein kinase activity in a biological sample, which comprises contacting said biological sample with a compound of any one of claims 1-22. 25. An in vitro method for inhibiting the kinase activity of the Tec family (Tec, Btk, Itk / Emt / Tsk, Bmx, Txk / Rlk) in a biological sample comprising contacting said biological sample with a compound of a any of claims 1-22. 5 10 fifteen twenty 25 30 35

26.

The method of claim 25, wherein the kinase activity of the Tec family is that of Itk kinase.

27.

The use of a compound of claims 1-22 for the preparation of a medicament for treating autoimmune, inflammatory, proliferative or hyperproliferative diseases or a disease with immunological intervention.

28.

The use of claim 27, wherein an additional therapeutic agent is selected that is selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyper-proliferative disease, a disease with immune intervention, rejection of transplanted organs or tissues and acquired immunodeficiency syndrome (AIDS), wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single or separately pharmaceutical form of said composition as part of a multiple pharmaceutical form.

29.

The use of claims 27 and 28 wherein the autoimmune, inflammatory, proliferative or hyperproliferative disease or disease with immune intervention is selected from asthma, acute rhinitis, allergic rhinitis, atrophic, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidoysis, lung of peasant, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathies, ankylosing spondylitis, psoriatic arthritis and Reiter's disease, Behcet's disease, Sjogren's syndrome, generalized sclerosis, psoriasis, generalized sclerosis, other atopic dermatitis, dermatitis eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, vesicular pemphigus, bullous epidermolysis, urticaria, angioderma, vasculitis, erythema, cutaneous eosinophilias, uveitis, alopecia areata, spring conjunctivitis, celiac disease, proctitis, pancreatitis, gastritis, pancreatitis, gastroenteritis, gastritis Crohn's disease, ulcerative colitis, food related allergies, multiple sclerosis, arteriosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, disseminated lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper IgE syndrome, lepromatous leprosy, Sezary syndrome and idiopathic thrombocytopenic purpura, post-angioplasty restenosis, tumors, arteriosclerosis and disseminated lupus erythematosus, allograft rejection, acute and chronic allograft rejection after kidney transplantation, heart, liver, liver , bone marrow, skin and cornea; or graft versus host disease, which comprises administering to a patient in need thereof a compound of claim 1.

30

A procedure for preparing a compound of formula 4:

image 1 that understands a) reacting a compound of formula 1 with an appropriate boronic acid precursor under Pd coupling conditions to form a compound of formula 2; image 1 b) coupling the compound of formula 2, wherein Z is as defined according to any one of claims 1-22 and W is F or an alkoxy; with R2-hal, wherein R2 is according to any one of claims 1-22 and hal is halogen, to form a compound of formula 3: image 1 wherein R2, W and Z are as defined according to any one of claims 1-22; c) heating the compound of formula 3 under acidic conditions to form a compound of formula 4 wherein Z and R2 are as defined according to one of claims 1-22.